Summary
Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease—ie, plaques, composed of amyloid β (Aβ), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Aβ metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Physiological (and pharmacological) changes in neuronal activity, especially synaptic activity, may continuously alter the levels of both A40 and the far more amyloidogenic A42 species in brain regions prone to formation of amyloid plaques.

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.

The promise of disease-modifying treatments for Alzheimer disease calls for biomarkers that enable early diagnosis. A new discovery shows how to visualize amyloid pathology in living Alzheimer patients.

In a recent paper(Klunk, W.E. et al. Ann. Neurol. 55, 306–319 (2004). ), Klunk and coworkers introduced amyloid imaging as a new principle, enabling direct visualization of amyloid plaques in the living human brain. Using a novel positron emission tomography (PET) tracer called Pittsburgh Compound-B (PIB), the authors found marked retention of the molecule in Alzheimer disease patients in areas of the brain known to contain large amounts of A plaques.

From imaging to immunotherapy, and synapses to -secretase: these are among the most exciting findings in the field of Alzheimer disease from the past three years, according to leading scientists. Many hope that these discoveries will soon lead to a cure for this devastating illness, which affects approximately 4.5 million individuals in the US alone. In countries such as Japan, where the proportion of aged individuals is expected to almost double over the next 50 years, tackling Alzheimer disease is crucial for safeguarding the health of the population...........